Two epithelial cell states have been identified that can help to distinguish between types of uterine cancer, British researchers announced last night.
A study by the Wellcome Sanger Institute, the University of Cambridge and their collaborators is the first reference map of the uterus to combine single cell and spatial transcriptomics, which has provided detailed descriptions of cell types as well as where they are located in the womb lining.
The research, published yesterday in Nature Genetics as part of the Human Cell Atlas, revealed the new cell types are in the endometrium.
The team analysed uterine samples from 15 women of reproductive age using single-cell and spatial transcriptomics, which enabled them to generate a cellular map of the human endometrium that accounted for the dynamic changes during the menstrual cycle.
The two new cell states have been identified as SOX9+LGR5+ and SOX9+LGR5 and these become more numerous as the epithelium regenerates during the menstrual cycle.
The researchers discovered the relative populations of these two cells were connected with two types of endometrial cancer, and the tumours carried a higher proportion of SOX9+LGR5+, which is associated with more severe disease.
Senior author Dr Roser Vento-Tormo, of the Wellcome Sanger Institute, said: “We have discovered two new epithelial cell states, and revealed that enrichment of the SOX9+LGR5+ cell population is associated with later stage cancers that pose a greater threat to the patient, as compared to tumours with higher levels of SOX9+LGR5-cells. Understanding the type and severity of a cancer can be crucial in deciding the best course of treatment.”
The majority of the epithelial cells in the endometrium are secretory or ciliated cells and this study used spatial transcriptomic data to identify cell signal pathways in the endometrial glands and lumen that differentiate between them, the researchers say.
These NOTCH and WNT pathways determine whether or not a cell becomes a secretory cell, which are found more in the glands, or a ciliated cell, which are greater in the lumen.
The researchers used endometrial organoids to further dissect the molecular mechanisms involved in epithelial differentiation and these organoids responded to the ovarian hormones, oestrogen and progesterone, mimicking how endometrial tissues function in the body.
Senior author Dr Margherita Turco, from the University of Cambridge, said: “The benefit of combining single cell and spatial transcriptomics to dissect the heterogeneity of tissues is that you know which pieces make up a tissue as well as the instructions for how those pieces fit together.
“We used this information to create these distinct environments in our endometrial organoids. Both hormonal and local environment signals play roles in endometrium regeneration. By using both these cues in our organoid models, we open up new possibilities for understanding the endometrium in health and disease.”
Dr Sarah Teichmann, a senior author of the study from the Wellcome Sanger Institute and University of Cambridge, and co-chair of the Human Cell Atlas Organising Committee, said the Uterine Cell Atlas, and the sophisticated organoid models that have been created using these data, will help scientists to better understand the healthy endometrium and how things go wrong in disease.
Garcia-Alonso L, Handfield LF, Roberts K et al. Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro. Nature Genetics 2 December 2021
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